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Pressure ulcers (PUs) are a major public health challenge, having a significant impact on healthcare service and patient quality of life. Computational biomechanical modelling has enhanced PU research by facilitating the investigation of pressure responses in subcutaneous tissue and skeletal muscle. Extensive work has been undertaken on PUs on patients in the seated posture, but research into heel ulcers has been relatively neglected. The aim of this review was to address the key challenges that exist in developing an effective FE foot model for PU prevention and the confusion surrounding the wide range of outputs reported. Nine FE foot studies investigating heel ulcers in bedrest were identified and reviewed. Six studies modelled the posterior part of the heel, two included the calf and foot, and one modelled the whole body. Due to the complexity of the foot anatomy, all studies involved simplification or assumptions regarding parts of the foot structure, boundary conditions and material parameters. Simulations aimed to understand better the stresses and strains exhibited in the heel soft tissues of the healthy foot. The biomechanical properties of soft tissue derived from experimental measurements are critical for developing a realistic model and consequently guiding clinical decisions. Yet, little to no validation was reported in each of the studies. If FE models are to address future research questions and clinical applications, then sound verification and validation of these models is required to ensure accurate conclusions and prediction of patient outcomes. Recommendations and considerations for future FE studies are therefore proposed., (Copyright © 2021 Tissue Viability Society. Published by Elsevier Ltd. All rights reserved.)

Temperature and humidity conditions at the interface between a support surface and the skin, termed microclimate, has been implicated in the development of pressure ulcers. Support surface technologies have been developed to control microclimate conditions, although only a few standard test methods exist to evaluate their performance. This study describes a combined experimental-computational approach to analyzing microclimate control systems. The study used a modified physical model protocol to evaluate two specific support surface systems involving a spacer fabric cover with i) no air flow and ii) an active fan. The physical model deposited moisture at a controlled rate for 25 min, and the microclimate conditions under the model and the surrounding area were monitored for 24 h. Using the experimental data as boundary conditions, a finite element model was developed using mass transport principles, which was calibrated using experimental results. Model inputs included mass density and mass diffusivity, resulting in an estimated absolute humidity change over time. The physical model tests revealed distinct differences between the support surfaces with and without active airflow, with the former having little effect on local humidity levels (RH>75% for 24hr). By contrast, there was a spatial and temporal change in microclimate with the active fan, with sensors positioned towards the source of airflow reaching ambient conditions within 24hr. The computational model was refined to produce comparable results with respect to both the spatial distribution of microclimate and the change in values over time. The combined experimental and computation approach was able to distinguish distinct difference in microclimate change between two support surface designs. The approach could enable the efficient evaluation of different mattress design principles to aid decision making for personalized support surface solutions, for the prevention of pressure ulcers., (Copyright © 2021 Tissue Viability Society. Published by Elsevier Ltd. All rights reserved.)

Objective: Pressure ulcers are caused by prolonged mechanical loads deforming the underlying soft tissues. However, the mechanical loads for microcirculatory occlusion are unknown. The present study was designed to characterize the simultaneous response of microvascular and lymphatic structures under repeated mechanical loading., Methods: The effects of two distinct loading/unloading cycles involving (a) incremental pressures 30, 60, and 90 mmHg and (b) three repeated cycles of 30 mmHg were evaluated on a cohort of able-bodied volunteers. Microvascular response involved the monitoring of transcutaneous gas tensions, while dermal lymphatic activity was estimated from near-infrared imaging. Responses were compared during each load and recovery cycle., Results: Changes in microvascular response were dependent on the load magnitudes, with 30 mmHg resulting in a reduction in oxygen tension only, while 90 mmHg affected both oxygen and carbon dioxide values in most cases (54%). By contrast, lymphatics revealed near total occlusion at 30 mmHg. Although there were intersubject differences, temporal trends consistently revealed partial or full impairment under load, with recovery during off-loading., Conclusions: The pressure required to cause microcirculatory occlusion differed between individuals, with lymphatic impairment occurring at a lower pressure to that of microvascular vessels. This highlights the need for personalized care strategies and regular off-loading of vulnerable tissues., (© 2020 The Authors. Microcirculation published by John Wiley & Sons Ltd.)

Background: The heel is one of the most common sites of pressure ulcers and the anatomical location with the highest prevalence of deep tissue injury. Several finite element modeling studies investigate heel ulcers for bedridden patients. In the current study we have added the implementation of the calf structure to the current heel models. We tested the effect of foot posture, mattress stiffness, and a lateral calcaneus displacement to the contact pressure and internal maximum shear strain occurring at the heel., Methods: A new 3D finite element model is created which includes the heel and calf structure. Sensitivity analyses are performed for the foot orientation relative to the mattress, the Young's modulus of the mattress, and a lateral displacement of the calcaneus relative to the other soft tissues in the heel., Findings: The models predict that a stiffer mattress results in higher contact pressures and internal maximum shear strains at the heel as well as the calf. An abducted foot posture reduces the internal strains in the heel and a lateral calcaneus displacement increases the internal maximum shear strains. A parameter study with different mattress-skin friction coefficients showed that a coefficient below 0.4 decreases the maximum internal shear strains in all of the used loading conditions., Interpretation: In clinical practice, it is advised to avoid internal shearing of the calcaneus of patients, and it could be taken into consideration by medical experts and nurses that a more abducted foot position may reduce the strains in the heel., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Pressure ulcers (PUs) represent a substantial burden to both patients and healthcare providers. Accordingly, effective prevention strategies should follow early detection of PUs. Anaerobic metabolites, such as lactate and pyruvate, are promising noninvasive biomarkers indicative of tissue ischaemia, one of the major mechanisms leading to PU development. The aim of this study was to investigate if the temporal release profile of these metabolites in sweat and sebum is sensitive to detect local tissue changes resulting from prolonged mechanical loads. The sacrum of healthy volunteers was subjected to two different loading protocols. After a baseline measurement, the left and right side of the sacrum were subjected to continuous and intermittent loading regimen, respectively, at a pressure of 100 mmHg. Biomarker samples were collected every 20 min, with a total experimental time of 140 min. Sweat was collected at 37 ∘ C and 80% relative humidity, and sebum at ambient conditions, from 11 to 13 volunteers, respectively. Both samples were analysed for lactate and pyruvate concentrations using ultra-high performance supercritical fluid chromatography mass spectrometry. Prior to analysis metabolite concentrations were normalized to individual baseline levels and, in the case of sweat, additional normalization was performed to an unloaded control site to account for fatigue of sweat glands. Although substantial variability was present, the temporal release profiles of both sweat and sebum metabolites reflected the applied loading regimen with increased levels upon load application, and recovery to baseline levels following load removal. Highest relative increases were 20% and 30% for sweat lactate and pyruvate, respectively, and 41% for sebum lactate. Sebum pyruvate was not present in quantifiable amounts. There was a linear correlation between the individual responses to intermittent and continuous loading. The present study revealed that metabolite biomarkers in both sweat and sebum were sensitive to the application of mechanical loads, indicative of local ischaemia within skin and soft tissues. Similar trends in metabolic biomarkers were observed in response to intermittent and continuous loading regimens in both sweat and sebum. Metabolites represent a potential means to monitor the health of loaded skin and soft tissues informing timely interventions of PU prevention., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The current state-of-the-art diagnosis method for deep tissue injury in muscle, a subcategory of pressure ulcers, is palpation. It is recognized that deep tissue injury is frequently preceded by altered biomechanical properties. A quantitative understanding of the changes in biomechanical properties preceding and during deep tissue injury development is therefore highly desired. In this paper we quantified the spatial-temporal changes in mechanical properties upon damage development and recovery in a rat model of deep tissue injury. Deep tissue injury was induced in nine rats by two hours of sustained deformation of the tibialis anterior muscle. Magnetic resonance elastography (MRE), T 2 -weighted, and T 2 -mapping measurements were performed before, directly after indentation, and at several timepoints during a 14-day follow-up. The results revealed a local hotspot of elevated shear modulus (from 3.30 ± 0.14 kPa before to 4.22 ± 0.90 kPa after) near the center of deformation at Day 0, whereas the T 2 was elevated in a larger area. During recovery there was a clear difference in the time course of the shear modulus and T 2 . Whereas T 2 showed a gradual normalization towards baseline, the shear modulus dropped below baseline from Day 3 up to Day 10 (from 3.29 ± 0.07 kPa before to 2.68 ± 0.23 kPa at Day 10, P < 0.001), followed by a normalization at Day 14. In conclusion, we found an initial increase in shear modulus directly after two hours of damage-inducing deformation, which was followed by decreased shear modulus from Day 3 up to Day 10, and subsequent normalization. The lower shear modulus originates from the moderate to severe degeneration of the muscle. MRE stiffness values were affected in a smaller area as compared with T 2 . Since T 2 elevation is related to edema, distributing along the muscle fibers proximally and distally from the injury, we suggest that MRE is more specific than T 2 for localization of the actual damaged area., (© 2019 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)

Pressure-induced deep tissue injury is a form of pressure ulcer which is difficult to detect and diagnose at an early stage, before the wound has severely progressed and becomes visible at the skin surface. At the present time, no such detection technique is available. To test the hypothesis that muscle damage biomarkers can be indicative of the development of deep tissue injury after sustained mechanical loading, an indentation test was performed for 2 h on the tibialis anterior muscle of rats. Myoglobin and troponin were analysed in blood plasma and urine over a period of 5 days. The damage as detected by the biomarkers was compared to damage as observed with T 2 MRI to validate the response. We found that myoglobin and troponin levels in blood increased due to the damage. Myoglobin was also increased in urine. The amount of damage observed with MRI immediately after loading had a strong correlation with the maximal biomarker levels: troponin in blood r s = 0.94; myoglobin in blood r s = 0.75; and myoglobin in urine r s = 0.57. This study suggests that muscle damage markers measured in blood and urine could serve as early diagnosis for pressure induced deep tissue injury., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Deep tissue injury is a type of pressure ulcer which originates subcutaneously due to sustained mechanical loading. The relationship between mechanical compression and damage development has been extensively studied in 2D. However, recent studies have suggested that damage develops beyond the site of indentation. The objective of this study was to compare mechanical loading conditions to the associated damage in 3D., Methods: An indentation test was performed on the tibialis anterior muscle of rats (n = 39). Changes in the form of oedema and structural damage were monitored with MRI in an extensive region. The internal deformations were evaluated using MRI based 3D finite element models., Findings: Damage propagates away from the loaded region. The 3D analysis indicates that there is a subject specific tolerance to compression induced deep tissue injury., Interpretation: Individual tolerance is an important factor when considering the mechanical loading conditions which induce damage., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Pressure ulcers (PUs) are a major burden to both patients, carers and the healthcare system. It is therefore important to identify patients at risk and detect pressure ulcers at an early stage of their development. The pro-inflammatory cytokine IL-1α is a promising indicator of tissue damage. The aim of this study was to compare the temporal skin response, by means of IL-1α expression, to different loading regimens and to investigate the presence of individual variability. The sacrum of eleven healthy volunteers was subjected to two different loading protocols. After a baseline measurement, the left and right side of the sacrum were subjected to continuous and intermittent loading regimen, respectively, at a pressure of 100 mmHg. Data was collected every 20 min, allowing for a total experimental time of 140 min. Sebum, collected at ambient conditions using Sebutape, was analyzed for the pro-inflammatory cytokine IL-1α. Most robust results were obtained using a baseline normalization approach on individual data. The IL-1α level significantly changed upon load application and removal (p<0.05) for both loading regimens. Highest IL-1α ratio increase, 3.7-fold, was observed for 1 h continuous loading. During the refractory periods for both loading regimen the IL-1α levels were still found to be up-regulated compared to baseline (p<0.05). The IL-1α level increased significantly for the two initial loading periods (p<0.05), but stabilized during the final loading period for both loading regimens. Large individual variability in IL-1α ratio was observed in the responses, with median values of 1.91 (range 1.49-3.08), and 2.52 (range 1.96-4.29), for intermittent and continuous loading, respectively, although the differences were not statistically significant. Cluster analysis revealed the presence of two distinct sub-populations, with either a low or high response to the applied loading regimen. The measurement after the first loading period proved to be representative for the subsequent measurements on each site. This study revealed that trends in normalized IL-1α provided an early indicator for tissue status following periods of mechanical loading and refractory unloaded conditions. Additionally, the observed individual variability in the response potentially identifies patients at risk of developing PUs., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Pressure ulcers occur due to sustained mechanical loading. Deep tissue injury is a severe type of pressure ulcer, which is believed to originate in subcutaneous tissues adjacent to bony prominences. In previous experimental-numerical studies the relationship between internal tissue state and damage development was investigated using a 2D analysis. However, recent studies suggest that a local analysis is not sufficient. In the present study we developed a method to create animal-specific 3D finite element models of an indentation test on the tibialis anterior muscle of rats based on MRI data. A detailed description on how the animal specific models are created is given. Furthermore, two indenter geometries are compared and the influence of errors in determining the indenter orientation on the resulting internal strain distribution in a defined volume of tissue was investigated. We conclude that with a spherically-shaped indenter errors in estimating the indenter orientation do not unduly influence the results of the simulation.

Skin mechanics is of importance in various fields of research when accurate predictions of the mechanical response of skin is essential. This study aims to develop a new constitutive model for human skin that is capable of describing the heterogeneous, nonlinear viscoelastic mechanical response of human skin under shear deformation. This complex mechanical response was determined by performing large amplitude oscillatory shear (LAOS) experiments on ex vivo human skin samples. It was combined with digital image correlation (DIC) on the cross-sectional area to assess heterogeneity. The skin is modeled as a one-dimensional layered structure, with every sublayer behaving as a nonlinear viscoelastic material. Heterogeneity is implemented by varying the stiffness with skin depth. Using an iterative parameter estimation method all model parameters were optimized simultaneously. The model accurately captures strain stiffening, shear thinning, softening effect and nonlinear viscous dissipation, as experimentally observed in the mechanical response to LAOS. The heterogeneous properties described by the model were in good agreement with the experimental DIC results. The presented mathematical description forms the basis for a future constitutive model definition that, by implementation in a finite element method, has the capability of describing the full 3D mechanical behavior of human skin., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Ultrasonography may have potential as an effective diagnostic tool for deep tissue injury (DTI) in tissues overlying bony prominences that are vulnerable when under sustained loading in sitting. Methods: Three cases of DTI in the fat and muscle layers overlying the ischial tuberosity of the pelvis in 3 persons with spinal cord injury (SCI) with different medical histories and abnormal tissue signs are described. Conclusion: There is a need for prospective studies using a reliable standardized ultrasonography protocol to diagnose DTI and to follow its natural history to determine its association with the development of pressure injuries.

Contractile stress generation by adherent cells is largely determined by the interplay of forces within their cytoskeleton. It is known that actin stress fibers, connected to focal adhesions, provide contractile stress generation, while microtubules and intermediate filaments provide cells compressive stiffness. Recent studies have shown the importance of the interplay between the stress fibers and the intermediate filament vimentin. Therefore, the effect of the interplay between the stress fibers and vimentin on stress generation was quantified in this study. We hypothesized that net stress generation comprises the stress fiber contraction combined with the vimentin resistance. We expected an increased net stress in vimentin knockout (VimKO) mouse embryonic fibroblasts (MEFs) compared to their wild-type (vimentin wild-type (VimWT)) counterparts, due to the decreased resistance against stress fiber contractility. To test this, the net stress generation by VimKO and VimWT MEFs was determined using the thin film method combined with sample-specific finite element modeling. Additionally, focal adhesion and stress fiber organization were examined via immunofluorescent staining. Net stress generation of VimKO MEFs was three-fold higher compared to VimWT MEFs. No differences in focal adhesion size or stress fiber organization and orientation were found between the two cell types. This suggests that the increased net stress generation in VimKO MEFs was caused by the absence of the resistance that vimentin provides against stress fiber contraction. Taken together, these data suggest that vimentin resists the stress fiber contractility, as hypothesized, thus indicating the importance of vimentin in regulating cellular stress generation by adherent cells.

Early diagnosis of deep tissue injury remains problematic due to the complicated and multifactorial nature of damage induction and the many processes involved in damage development and recovery. In this paper, we present a comprehensive assessment of deep tissue injury development and remodeling in a rat model by multiparametric magnetic resonance imaging (MRI) and histopathology. The tibialis anterior muscle of rats was subjected to mechanical deformation for 2 h. Multiparametric in vivo MRI, consisting of T 2 , T 2 *, mean diffusivity (MD), and angiography measurements, was applied before, during, and directly after indentation as well as at several time points during a 14-day follow-up. MRI readouts were linked to histological analyses of the damaged tissue. The results showed dynamic change in various MRI parameters, reflecting the histopathological status of the tissue during damage induction and repair. Increased T 2 corresponded with edema, muscle cell damage, and inflammation. T 2 * was related to tissue perfusion, hemorrhage, and inflammation. MD increase and decrease was reported on the tissue's microstructural integrity and reflected muscle degeneration and edema as well as fibrosis. Angiography provided information on blockage of blood flow during deformation. Our results indicate that the effects of a single damage-causing event of only 2 h of deformation were present up to 14 days. The initial tissue response to deformation, as observed by MRI, starts at the edge of the indentation. The quantitative MRI readouts provided distinct and complementary information on the extent, temporal evolution, and microstructural basis of deep tissue injury-related muscle damage. NEW & NOTEWORTHY We have applied a multiparametric MRI approach linked to histopathology to characterize damage development and remodeling in a rat model of deep tissue injury. Our approach provided several relevant insights in deep tissue injury. Response to damage, as observed by MRI, started at some distance from the deformation. Damage after a single indentation period persisted up to 14 days. The MRI parameters provided distinct and complementary information on the microstructural basis of the damage.

Understanding cell contractility is of fundamental importance for cardiovascular tissue engineering, due to its major impact on the tissue's mechanical properties as well as the development of permanent dimensional changes, e.g., by contraction or dilatation of the tissue. Previous attempts to quantify contractile cellular stresses mostly used strongly aligned monolayers of cells, which might not represent the actual organization in engineered cardiovascular tissues such as heart valves. In the present study, therefore, we investigated whether differences in organization affect the magnitude of intrinsic stress generated by individual myofibroblasts, a frequently used cell source for in vitro engineered heart valves. Four different monolayer organizations were created via micro-contact printing of fibronectin lines on thin PDMS films, ranging from strongly anisotropic to isotropic. Thin film curvature, cell density, and actin stress fiber distribution were quantified, and subsequently, intrinsic stress and contractility of the monolayers were determined by incorporating these data into sample-specific finite element models. Our data indicate that the intrinsic stress exerted by the monolayers in each group correlates with cell density. Additionally, after normalizing for cell density and accounting for differences in alignment, no consistent differences in intrinsic contractility were found between the different monolayer organizations, suggesting that the intrinsic stress exerted by individual myofibroblasts is independent of the organization. Consequently, this study emphasizes the importance of choosing proper architectural properties for scaffolds in cardiovascular tissue engineering, as these directly affect the stresses in the tissue, which play a crucial role in both the functionality and remodeling of (engineered) cardiovascular tissues.

Background: High strain in soft tissues that overly bony prominences are considered a risk factor for pressure ulcers (PUs) following spinal cord impairment (SCI) and have been computed using Finite Element methods (FEM). The aim of this study was to translate a MRI protocol into ultrasound (US) and determine between-operator reliability of expert sonographers measuring diameter of the inferior curvature of the ischial tuberosity (IT) and the thickness of the overlying soft tissue layers on able-bodied (AB) and SCI using real-time ultrasound., Material and Methods: Part 1: Fourteen AB participants with a mean age of 36.7 ± 12.09 years with 7 males and 7 females had their 3 soft tissue layers in loaded and unloaded sitting measured independently by 2 sonographers: tendon/muscle, skin/fat and total soft tissue and the diameter of the IT in its short and long axis. Part 2: Nineteen participants with SCI were screened, three were excluded due to abnormal skin signs, and eight participants (42%) were excluded for abnormal US signs with normal skin. Eight SCI participants with a mean age of 31.6 ± 13.6 years and all male with 4 paraplegics and 4 tetraplegics were measured by the same sonographers for skin, fat, tendon, muscle and total. Skin/fat and tendon/muscle were computed., Results: AB between-operator reliability was good (ICC = 0.81-0.90) for 3 soft tissues layers in unloaded and loaded sitting and poor for both IT short and long axis (ICC = -0.028 and -0.01). SCI between-operator reliability was good in unloaded and loaded for total, muscle, fat, skin/fat, tendon/muscle (ICC = 0.75-0.97) and poor for tendon (ICC = 0.26 unloaded and ICC = -0.71 loaded) and skin (ICC = 0.37 unloaded and ICC = 0.10)., Conclusion: A MRI protocol was successfully adapted for a reliable 3 soft tissue layer model and could be used in a 2-D FEM model designed to estimate soft tissue strain as a novel risk factor for the development of a PU., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Spinal immobilisation using a rigid long spineboard is a well-established procedure in trauma care. During immobilisation, the body is exposed to high tissue-interface pressures. This may lead to a localised inflammatory response of the skin, which may be used to monitor the body's response to different types of immobilisation device., Aim: In this study we compared the standard rigid spineboard with a new soft-layered spineboard regarding tissue-interface pressures, skin redness as an indicator of reactive hyperaemia and cutaneous IL1α and lactate release., Methods: Twelve healthy male participants were asked to lie supine on both a rigid and a soft-layered spineboard, loading the sacrum for one hour, followed by one hour in unloaded position. Tissue-interface pressures on the buttocks during loading were measured continuously using a pressure mapping mat. Cutaneous IL1α and lactate concentrations were assessed using Sebutapes, during 20-min periods. After each 20-min period, a photo of the buttocks was taken, which was later assessed for redness by two observers., Results: Significant differences in tissue-interface pressure and reactive hyperaemia were found between the two types of spineboard. Release of IL1α and lactate were found to increase with prolonged exposure to pressure, and to decrease in the unloaded prone position. A significant relationship was found between tissue-interface pressure and reactive hyperaemia, but not with IL1α nor lactate release. Time course of IL1α and lactate release was similar for both types of spineboard., Conclusions: IL1α and lactate both have a strong relationship with pressure exposure time, but not with pressure magnitude. Furthermore, IL1α was measured even in the absence of visible redness of the skin. The study offers the potention of biomarkers, reflecting inflammation and/or tissue metabolism, for use in assessing the effects of prolonged spineboard support., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

One of the hallmarks of biological soft tissues is their capacity to grow and remodel in response to changes in their environment. Although it is well-accepted that these processes occur at least partly to maintain a mechanical homeostasis, it remains unclear which mechanical constituent(s) determine(s) mechanical homeostasis. In the current study a nondestructive mechanical test and a two-step inverse analysis method were developed and validated to nondestructively estimate the mechanical properties of biological tissue during tissue culture. Nondestructive mechanical testing was achieved by performing an inflation test on tissues that were cultured inside a bioreactor, while the tissue displacement and thickness were nondestructively measured using ultrasound. The material parameters were estimated by an inverse finite element scheme, which was preceded by an analytical estimation step to rapidly obtain an initial estimate that already approximated the final solution. The efficiency and accuracy of the two-step inverse method was demonstrated on virtual experiments of several material types with known parameters. PDMS samples were used to demonstrate the method's feasibility, where it was shown that the proposed method yielded similar results to tensile testing. Finally, the method was applied to estimate the material properties of tissue-engineered constructs. Via this method, the evolution of mechanical properties during tissue growth and remodeling can now be monitored in a well-controlled system. The outcomes can be used to determine various mechanical constituents and to assess their contribution to mechanical homeostasis., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Atherosclerotic plaque rupture is the primary trigger of fatal cardiovascular events. Fibrillar collagen in atherosclerotic plaques and their directionality are anticipated to play a crucial role in plaque rupture. This study aimed assessing 3D fiber orientations and architecture in atherosclerotic plaques for the first time. Seven carotid plaques were imaged ex-vivo with a state-of-the-art Diffusion Tensor Imaging (DTI) technique, using a high magnetic field (9.4Tesla) MRI scanner. A 3D spin-echo sequence with uni-polar diffusion sensitizing pulsed field gradients was utilized for DTI and fiber directions were assessed from diffusion tensor measurements. The distribution of the 3D fiber orientations in atherosclerotic plaques were quantified and the principal fiber orientations (circumferential, longitudinal or radial) were determined. Overall, 52% of the fiber orientations in the carotid plaque specimens were closest to the circumferential direction, 34% to the longitudinal direction, and 14% to the radial direction. Statistically no significant difference was measured in the amount of the fiber orientations between the concentric and eccentric plaque sites. However, concentric plaque sites showed a distinct structural organization, where the principally longitudinally oriented fibers were closer to the luminal side and the principally circumferentially oriented fibers were located more abluminally. The acquired unique information on 3D plaque fiber direction will help understanding pathobiological mechanisms of atherosclerotic plaque progression and pave the road to more realistic biomechanical plaque modeling for rupture assessment., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

In order to maintain tissue homeostasis and functionality, adherent cells need to sense and respond to environmental mechanical stimuli. An important ability that adherent cells need in order to properly sense and respond to mechanical stimuli is the ability to exert contractile stress onto the environment via actin stress fibers. The actin stress fibers form a structural chain between the cells' environment via focal adhesions and the nucleus via the nuclear lamina. In case one of the links in this chain is missing or aberrant, contractile stress generation will be affected. This is especially the case in laminopathic cells, which have a missing or mutated form of the LMNA gene encoding for part of the nuclear lamina. Using the thin film method combined with sample specific finite element modeling, we quantitatively showed a fivefold lower contractile stress generation of Lmna knockout mouse embryonic fibroblasts (MEFs) as compared to wild-type MEFs. Via fluorescence microscopy it was demonstrated that the lower contractile stress generation was associated with an impaired actin stress fiber organization with thinner actin fibers and smaller focal adhesions. Similar experiments with wild-type MEFs with chemically disrupted actin stress fibers verified these findings. These data illustrate the importance of an organized actin stress fiber network for contractile stress generation and demonstrate the devastating effect of an impaired stress fiber organization in laminopathic fibroblasts. Next to this, the thin film method is expected to be a promising tool in unraveling contractility differences between fibroblasts with different types of laminopathic mutations.

The evolution of minimally invasive implantation procedures and the in vivo remodeling potential of decellularized tissue-engineered heart valves require stents with growth capacity to make these techniques available for pediatric patients. By means of computational tools and 3D printing technology, this proof-of-concept study demonstrates the design and manufacture of a polymer stent with a mechanical performance comparable to that of conventional nitinol stents used for heart valve implantation in animal trials. A commercially available 3D printing polymer was selected, and crush and crimping tests were conducted to validate the results predicted by the computational model. Finally, the degradability of the polymer was assessed via accelerated hydrolysis., Competing Interests: No competing financial interests exist., (© María Sol Cabrera, et al., 2017; Published by Mary Ann Liebert, Inc.)

Deep tissue injury (DTI), a type of pressure ulcer, arises in the muscle layers adjacent to bony prominences due to sustained mechanical loading. DTI presents a serious problem in the clinic, as it is often not visible until reaching an advanced stage. One of the causes can be direct mechanical deformation of the muscle tissue and cell. The mechanism of cell death induced by mechanical compression was studied using bio-artificial skeletal muscle tissues. Compression was applied by placing weights on top of the constructs. The morphological changes of the cytoskeleton and the phosphorylation of mitogen-activated protein kinases (MAPK) under compression were investigated. Moreover, inhibitors for each of the three major MAPK groups, p38, ERK, and JNK, were applied separately to look at their roles in the compression caused apoptosis and necrosis. The present study for the first time showed that direct mechanical compression activates MAPK phosphorylation. Compression also leads to a gradual destruction of the cytoskeleton. The percentage apoptosis is strongly reduced by p38 and JNK inhibitors down to the level of the unloaded group. This phenomenon could be observed up to 24h after initiation of compression. Therefore, cell death in bio-artificial muscle tissue caused by mechanical compression is primarily caused by a physiological mechanism, rather than through a physical mechanism which kills the cell directly. These findings reveal insight of muscle cell death under mechanical compression. Moreover, the result indicates a potential clinical solution to prevent DTI by pre-treating with p38 or/and JNK inhibitors., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Microneedles represent promising tools for delivery of drugs to the skin. However, before these microneedles can be used in clinical practice, it is essential to understand the process of skin penetration by these microneedles. The present study was designed to monitor both penetration depth and force of single solid microneedles with various tip diameters ranging from 5 to 37µm to provide insight into the penetration process into the skin of these sharp microneedles. To determine the microneedle penetration depth, single microneedles were inserted in human ex vivo skin while monitoring the surface of the skin. Simultaneously, the force on the microneedles was measured. The average penetration depth at 1.5mm displacement was similar for all tip diameters. However, the process of penetration depth was significantly different for the various microneedles. Microneedles with a tip diameter of 5µm were smoothly inserted into the skin, while the penetration depth of microneedles with a larger tip diameter suddenly increased after initial superficial penetration. In addition, the force at insertion (defined as the force at a sudden decrease in measured force) linearly increased with tip diameter ranging from 20 to 167mN. The force drop at insertion was associated with a measured penetration depth of approximately 160μm for all tip diameters, suggesting that the drop in force was due to the penetration of a deeper skin layer. This study showed that sharp microneedles are essential to insert microneedles in a well-controlled way to a desired depth., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Electrospinning has proven to be a promising method to produce scaffolds for tissue engineering despite the frequently encountered limitations in 3-dimensional tissue formation due to a lack of cell infiltration. To fully unlock the potential of electrospun scaffolds for tissue engineering, the void space within the fibrous network needs to be increased substantially and in a controlled manner. Low-temperature electrospinning (LTE) increases the fiber to fiber distance by embedding ice particles as void spacers during fiber deposition. Scaffold porosities up to 99.5% can be reached and in line with the increase in void space, the mechanical properties of the scaffolds shift towards the range for native biological tissue. While both the physiological mechanical properties and high porosity were promising for tissue engineering applications, control of the porosity in three dimensions was still limited when using LTE methods. Based on a range of LTE spun scaffolds made of poly(lactic acid) and poly(ε-caprolactone), we found that changing the ratio between the rate of ice crystal formation and polymer fiber deposition only had a small effect on the 3D-porosity of the final scaffold architecture. Varying the fiber stiffness, however, offers considerable control over the scaffold void space.